TY - JOUR
T1 - Active solubilization and refolding of stable protein aggregates by cooperative unfolding action of individual Hsp70 chaperones
AU - Ben-Zvi, Anat
AU - De Los Rios, Paolo
AU - Dietler, Giovanni
AU - Goloubinoff, Pierre
PY - 2004/9/3
Y1 - 2004/9/3
N2 - Hsp70 is a central molecular chaperone that passively prevents protein aggregation and uses the energy of ATP hydrolysis to solubilize, translocate, and mediate the proper refolding of proteins in the cell. Yet, the molecular mechanism by which the active Hsp70 chaperone functions are achieved remains unclear. Here, we show that the bacterial Hsp70 (DnaK) can actively unfold misfolded structures in aggregated polypeptides, leading to gradual disaggregation. We found that the specific unfolding and disaggregation activities of individual DnaK molecules were optimal for large aggregates but dramatically decreased for small aggregates. The active unfolding of the smallest aggregates, leading to proper global refolding, required the cooperative action of several DnaK molecules per misfolded polypeptide. This finding suggests that the unique ATP-fueled locking/unlocking mechanism of the Hsp70 chaperones can recruit random chaperone motions to locally unfold misfolded structures and gradually disentangle stable aggregates into refoldable proteins.
AB - Hsp70 is a central molecular chaperone that passively prevents protein aggregation and uses the energy of ATP hydrolysis to solubilize, translocate, and mediate the proper refolding of proteins in the cell. Yet, the molecular mechanism by which the active Hsp70 chaperone functions are achieved remains unclear. Here, we show that the bacterial Hsp70 (DnaK) can actively unfold misfolded structures in aggregated polypeptides, leading to gradual disaggregation. We found that the specific unfolding and disaggregation activities of individual DnaK molecules were optimal for large aggregates but dramatically decreased for small aggregates. The active unfolding of the smallest aggregates, leading to proper global refolding, required the cooperative action of several DnaK molecules per misfolded polypeptide. This finding suggests that the unique ATP-fueled locking/unlocking mechanism of the Hsp70 chaperones can recruit random chaperone motions to locally unfold misfolded structures and gradually disentangle stable aggregates into refoldable proteins.
UR - http://www.scopus.com/inward/record.url?scp=4444288866&partnerID=8YFLogxK
U2 - 10.1074/jbc.M405627200
DO - 10.1074/jbc.M405627200
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C2 - 15201275
AN - SCOPUS:4444288866
SN - 0021-9258
VL - 279
SP - 37298
EP - 37303
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 36
ER -